Previous studies in this laboratory have shown that a number of physiological and nonphysiological iron-dependent mixed-function oxidation (MFO) systems catalyze the generation of highly reactive oxygen species (viz, free-radicals, ferryl ion) which can damage proteins. Further investigations have shown that : (a) MFO-catalyzed oxidative damage to proteins is partly responsible for the increase in levels of catalytically inactive or less active forms of enzymes that occur during aging and oxidative stress; (b) the copper-zinc superoxide dismutase which is believed to protect cells from superoxide anion radical damage can in fact under some physiological conditions (i.e., in the presence of bicarbonate ion and hydrogen peroxide) catalyze the formation of the even more damaging hydroxyl radical ; (c) protein oxidation and concomitant loss of glutamine synthetase activity occurs during reperfusion following ischemia of the gerbil brain; (d) the ischemia-reperfusion-mediated protein damage can be attenuated by the addition of the free radical spin-trap N-tert-butyl-alpha-phenylnitrone (PBN) to the reperfusion medium; (e) exposure of some proteins to ozone leads to rapid loss of tyrosine, histidine and methionine residues, whereas these same residues in other proteins are resistant to attack by ozone.